The long-term objective of this project is to develop small molecule inhibitors of TCR:MHC class II-peptide interactions for the treatment of multiple sclerosis (MS). The strong genetic association between specific MHC class ll alleles, such as HLA-DR2 (DRB1*1501), and susceptibility to MS provides support to a mechanism in which disease-associated MHC molecules selectively present myelin antigens that activate CD4 T cells. The hypothesis of this project is that small molecules that block TCR:HLA-DR2/peptide complex formation can prevent autoreactive T cell activation and chronic inflammatory processes in MS lesions. The investigator has developed sensitive screening assays to detect TCR:HLA-DR2/peptide interactions and methods to produce sufficient amounts of soluble and functional TCR and HLA-DR2/peptide reagents to support analysis of librarys of small molecules. Preliminary studies with another TCR:pMHC pair demonstrate that compounds that inhibit TCR:pMHC interaction can be identified using these screening methods. The specific aims of the project are to further develop high-throughput screening assays to identify and characterize small molecules that inhibit TCR:HLA-DR2/peptide interactions, to examine a large and diverse collection of small molecules for inhibitory activity and to test the immunosuppressive effects of these compounds in T cell-based assays. The results from these studies will provide useful information about TCR:pMHC interactions and could form the basis of a novel class of immunosuppressive drugs to treat human T-cell mediated autoimmune diseases.